Lenalidomide (Revlimid®, made by Celgene Corporation) is an orally available thalidomide analog and has been approved by the U.S. Food and Drug Administration for use in patients with multiple myeloma and myelodysplastic syndromes. In 2009, sales of Revlimid® reached USD $ 1.7 billion and sales in 2010 are expected to exceed USD $2.0 billion, making Revlimid® one of the most successful oncology products introduced into commerce in the past five years.
Lenalidomide has direct anti-tumor effect, inhibition of the microenvironment support for tumor cells, and immunomodulatory role and exerts anti-angiogenic and immunomodulatory/anti-inflammatory properties. However, Revlimid® is sold under an FDA mandated risk mitigation program with a ‘Black Box Warning’ describing the risks of birth defects because of thalidomide's well-known teratogenic effects. The protein target responsible for the teratogenicity of thalidomide was published as Cereblon (Ito et al, Science 327:1345-1350 (2010), Y. X. Zhu et al, 13th International Myeloma Workshop O-05 (2011)); however, the anticancer target(s) of Immunomodulatory drugs (IMiD's) are still unknown.
PRPK and TPRKB, are evolutionarily conserved from archaea and yeast to humans; yet very little is known about the function of these proteins, especially in humans. In yeast and archaea, Bud32 and Cgi121 (PRPK and TPRKB, respectively) have previously been demonstrated to form a functional complex named KEOPS with two other proteins called Kae1 and Pcc1. The yeast KEOPS complex is required for telomere maintenance and transcriptional regulation. The structure of the KEOPS complex has been studied by crystallography, although the proteins were of mixed origin (mostly archaea). Structure-based sequence alignments indicate that Bud32 (PRPK) is an atypical kinase that possesses an architecture characteristic of protein kinases but lacks an activation loop that is normally responsible for substrate recognition. PRPK and TPRKB are co-expressed in human cell line. PRPK and TPRKB are proteins relating to p53 in human. PRPK is TP53-regulating kinase protein and TPRKB is p53-related protein kinase-binding protein. However, formation and biological function of the human KEOPS complex has not been reported.